Biosynthesis of Hesperetin, Homoeriodictyol, and Homohesperetin in a Transcriptomics-Driven Engineered Strain of Streptomyces albidoflavus.

Flavonoids exhibit various bioactivities including anti-oxidant, anti-tumor, anti-inflammatory, and anti-viral properties. Methylated flavonoids are particularly significant due to their enhanced oral bioavailability, improved intestinal absorption, and greater stability. The heterologous production of plant flavonoids in bacterial factories involves the need for enough biosynthetic precursors to allow for high production levels. These biosynthetic precursors are malonyl-CoA and l-tyrosine. In this work, to enhance flavonoid biosynthesis in Streptomyces albidoflavus, we conducted a transcriptomics study for the identification of candidate genes involved in l-tyrosine catabolism. The hypothesis was that the bacterial metabolic machinery would detect an excess of this amino acid if supplemented with the conventional culture medium and would activate the genes involved in its catabolism towards energy production. Then, by inactivating those overexpressed genes (under an excess of l-tyrosine), it would be possible to increase the intracellular pools of this precursor amino acid and eventually the final flavonoid titers in this bacterial factory. The RNAseq data analysis in the S. albidoflavus wild-type strain highlighted the hppD gene encoding 4-hydroxyphenylpyruvate dioxygenase as a promising target for knock-out, exhibiting a 23.2-fold change (FC) in expression upon l-tyrosine supplementation in comparison to control cultivation conditions. The subsequent knock-out of the hppD gene in S. albidoflavus resulted in a 1.66-fold increase in the naringenin titer, indicating enhanced flavonoid biosynthesis. Leveraging the improved strain of S. albidoflavus, we successfully synthesized the methylated flavanones hesperetin, homoeriodictyol, and homohesperetin, achieving titers of 2.52 mg/L, 1.34 mg/L, and 0.43 mg/L, respectively. In addition, the dimethoxy flavanone homohesperetin was produced as a byproduct of the endogenous metabolism of S. albidoflavus. To our knowledge, this is the first time that hppD deletion was utilized as a strategy to augment the biosynthesis of flavonoids. Furthermore, this is the first report where hesperetin and homoeriodictyol have been synthesized from l-tyrosine as a precursor. Therefore, transcriptomics is, in this case, a successful approach for the identification of catabolism reactions affecting key precursors during flavonoid biosynthesis, allowing the generation of enhanced production strains.

RESOLUTION OF CALVARIAL HYPEROSTOSIS IN AFRICAN LION CUBS (PANTHERA LEO LEO) AFTER VITAMIN A SUPPLEMENTATION.

Two female (FL 1, FL 2) and one male (ML) 11-wk-old, intact, captive African lion cubs (Panthera leo leo) were presented with a history of mild vestibular signs. Initial serum vitamin A concentrations were low (140 nmol/L) for ML. Calvarial hyperostosis was confirmed using computed tomography (CT) of the head and cervical vertebrae in each cub. CT measurements were adapted in relation to the skull width. ML showed the most pronounced thickening of the tentorium cerebelli and occipital bone, represented by a tentorium cerebelli to skull width ratio (TCR) of 0.08 (FL 1: 0.06, FL 2: 0.05) and a basisphenoid to skull width ratio (BBR) of 0.07 (FL 1: 0.06, FL 2: 0.04). Magnetic resonance imaging (MRI) revealed cerebellar herniation and cervical intramedullary T2-weighted hyperintensity from C1, extending caudally for at least two cervical vertebrae in all cubs. Treatment was initiated with subcutaneous vitamin A supplementation and feeding of whole carcasses. Improvement in ataxia was noticed 3 wk later. Follow-up CT and MRI examinations were performed in ML after 3 and 8 mon. The affected bones appeared slightly less thickened and TCR and BBR had decreased to 0.05 after 3 mon. The cerebellum remained mildly herniated, accompanied by amelioration of cervical T2w hyperintensities. After 8 mon, evaluation and diagnostic imaging revealed further improvement regarding the neurologic status and measurements (TCR 0.05, BBR 0.04) despite persistence of a subtle cerebellar herniation. In conclusion, bone remodeling and improvement in clinical signs may be achievable in young lion cubs presented with calvarial hyperostosis and may be attributable to high-dose vitamin A supplementation.

Dietary supplementation of magnolol alleviates fatty liver hemorrhage syndrome in postpeak Xinhua laying hens via regulation of liver lipid metabolism.

As a metabolic disease, fatty liver hemorrhagic syndrome (FLHS) has emerged as a major cause of noninfectious mortality in laying hens, resulting in substantial economic losses to the poultry industry. This study aimed to investigate the therapeutic effects of magnolol on FLHS in postpeak laying hen model, focusing on lipid metabolism, antioxidative capacity, and potential molecular mechanisms of action. We selected 150 Xinhua laying hens aged 50 wk and divided them into normal diet group (ND), high-fat diet group (HFD), 100 mg/kg magnolol group (MG100), 300 mg/kg magnolol group (MG300), 500 mg/kg magnolol group (MG500) on average. The experiment lasted for 6 wk, and liver samples were collected from the hens at the end of the experiment. The results demonstrated that the inclusion of magnolol in the diet had a significant impact on various factors. It led to a reduction in weight, an increase in egg production rate, a decrease in blood lipid levels, and an improvement in abnormal liver function, liver steatosis, and oxidative stress. These effects were particularly prominent in the MG500 group. The RNA-Seq analysis demonstrated that in the MG500 group, there was a down-regulation of genes associated with fatty acid synthesis (Acc, Fasn, Scd, Srebf1, Elovl6) compared to the HFD group. Moreover, genes related to fatty acid oxidation (CPT1A and PGC1α) were found to be up-regulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these differentially expressed genes indicated their enrichment in the PPAR signaling pathway. These findings demonstrate that magnolol can mitigate FLHS by inhibiting fatty acid synthesis and promoting fatty acid oxidation. This discovery offers a novel approach for treating FLHS in laying hens, reducing the economic losses associate with FLHS.

Enrichment efficiency of lutein in eggs and its function in improving fatty liver hemorrhagic syndrome in aged laying hens.

In this study, we evaluated the enrichment efficiency of lutein in eggs and its function in preventing fatty liver hemorrhagic syndrome (FLHS) in aged laying hens. Five groups of laying hens (65 wk old) were fed basal diets supplemented with 0, 30, 60, 90, or 120 mg/kg of lutein. The supplementation period lasted 12 wk followed by 2 wk of lutein depletion in feed. The results revealed that lutein efficiently enriched the egg yolks and improved their color with a significant increase in relative redness (P < 0.001). Lutein accumulation increased in the egg yolk until day 10, then depletion reached a minimum level after 14 d. Overall, zeaxanthin content in all the groups was similar throughout the experimental period. However, triglycerides and total cholesterol were significantly decreased in the liver (P < 0.05) but not significantly different in the serum (P > 0.05). In the serum, the lipid metabolism enzyme acetyl-CoA synthetase was significantly reduced (P < 0.05), whereas dipeptidyl-peptidase 4 was not significantly different (P > 0.05), and there was no statistical difference of either enzyme in the liver (P > 0.05). Regarding oxidation and inflammation-related indexes, malondialdehyde, tumor necrosis factors alpha, interleukin-6, and interleukin-1 beta were decreased, whereas superoxide dismutase and total antioxidant capacity increased in the liver (P < 0.001). The function of lutein for the same indexes in serum was limited. It was concluded that lutein efficiently enriched the egg yolk of old laying hens to improve their color and reached the highest level on day 10 without being subject to a significant conversion into zeaxanthin. At the same time, lutein prevented liver steatosis in aged laying hens by exerting strong antioxidant and anti-inflammatory functions, but also through the modulation of lipid metabolism, which may contribute to reducing the incidence of FLHS in poultry.

Dehydroepiandrosterone activates the GPER-mediated AMPK signaling pathway to alleviate the oxidative stress and inflammatory response in laying hens fed with high-energy and low-protein diets.

Fatty liver hemorrhagic syndrome (FLHS) seriously threatens the layer industry due to it can cause a sudden decline in egg production and acute death, and dietary supplement with bioactive substance is considered an effective way to prevent the FLHS occurrence. Dehydroepiandrosterone (DHEA) is a popular dietary supplement and it possesses anti-oxidative and anti-inflammatory functions; however, the effect and underlying mechanism about DHEA in protecting against the occurrence and development of FLHS remain elucidated. The current results showed that DHEA relieved HELP-induced decrease of egg productivity and liver injury in laying hens. Meanwhile, DHEA markedly enhanced the antioxidant capacity and then alleviated oxidative stress via activation of nuclear factor (erythroid-derived 2)-like 2 (NRF-2) signal in laying hens fed with HELP diets. In addition, DHEA significantly alleviated HELP-stimulated systemic inflammatory response by suppressing the overproduction of hepatic pro-inflammatory factors in laying hens, and further found this beneficial effect was achieved by blocking the activation of NF-κB pathway. Furthermore, we found that DHEA promoted the AMP-activated protein kinase α (AMPKα) activation and increased the G-protein-coupled estrogen receptor (GPER) expression level in laying hens fed with HELP diets. In summary, our data demonstrated that DHEA attenuates oxidative stress and inflammation through the activation of GPER-AMPK signal axis in laying hens fed with HELP diets. These results might facilitate an understanding of the benefits and mechanism of DHEA on the development of FLHS, and provide sufficient data to support it as a dietary supplement to control the FLHS-related metabolic diseases in chickens.

Dietary supplementation of salidroside alleviates liver lipid metabolism disorder and inflammatory response to promote hepatocyte regeneration via PI3K/AKT/Gsk3-ß pathway.

Fatty liver hemorrhagic syndrome (FLHS) is a chronic hepatic disease which occurs when there is a disorder in lipid metabolism. FLHS is often observed in caged laying hens and characterized by a decrease in egg production and dramatic increase of mortality. Salidroside (SDS) is an herbal drug which has shown numerous pharmacological activities, such as protecting mitochondrial function, attenuating cell apoptosis and inflammation, and promoting antioxidant defense system. We aimed to determine the therapeutic effects of SDS on FLHS in laying hens and investigate the underlying mechanisms through which SDS operates these functions. We constructed oleic acid (OA)-induced fatty liver model in vitro and high-fat diet-induced FLHS of laying hens in vivo. The results indicated that SDS inhibited OA-induced lipid accumulation in chicken primary hepatocytes, increased hepatocyte activity, elevated the mRNA expression of proliferation related genes PCNA, CDK2, and cyclinD1 and increased the protein levels of PCNA and CDK2 (P < 0.05), as well as decreased the cleavage levels of Caspase-9, Caspase-8, and Caspase-3 and apoptosis in hepatocytes (P < 0.05). Moreover, SDS promoted the phosphorylation levels of PDK1, AKT, and Gsk3-ß, while inhibited the PI3K inhibitor (P < 0.05). Additionally, we found that high-fat diet-induced FLHS hens had heavier body weight, liver weight, and abdominal fat weight, and severe steatosis in histology, compared with the control group (Con). However, hens fed with SDS maintained lighter body weight, liver weight, and abdominal fat weight, as well as normal liver without hepatic steatosis. In addition, high-fat diet-induced FLHS hens had high levels of serum total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), and aspartate aminotransferase (AST) compared to the Con group, however, in the Model+SDS group, the levels of TC, TG, ALT, and AST decreased significantly, whereas the level of superoxide dismutase (SOD) increased significantly (P < 0.05). We also found that SDS significantly decreased the mRNA expression abundance of PPARγ, SCD, and FAS in the liver, as well as increased levels of PPARα and MTTP, and decreased the mRNA expression of TNF-α, IL-1ß, IL-6, and IL-8 in the Model+SDS group (P < 0.05). In summary, this study showed that 0.3 mg/mL SDS attenuated ROS generation, inhibited lipid accumulation and hepatocyte apoptosis, and promoted hepatocyte proliferation by targeting the PI3K/AKT/Gsk3-ß pathway in OA-induced fatty liver model in vitro, and 20 mg/kg SDS alleviated high-fat-diet-induced hepatic steatosis, oxidative stress, and inflammatory response in laying hens in vivo.

Alternativas terapéuticas para el síndrome de apnea e hipoapnea obstructiva del sueño en niños con anomalías intermaxilares sagitales o transversales: Revisión narrativa / Therapeutic alternatives for obstructive sleep apnea syndrome in children with sagittal and transverse intermaxillary anomalies: Narrative review

RESUMEN: Introducción: El síndrome de apnea e hipoapnea obstructiva del sueño corresponde a un trastorno respiratorio del sueño muy prevalente en niños. Muchas alternativas terapéuticas buscan controlar los factores desencadenantes y la progresión de los signos y síntomas. El objetivo de esta revisión es describir los efectos de los tratamientos para síndrome de apnea e hipoapnea del sueño en niños con anomalías intermaxilares sagitales o transversales. Material y método: Se realizó una búsqueda electrónica en las bases de datos: PubMed, Epistemónikos, EBSCO, TripDataBase y The Cochrane Library, con las palabras clave: "Obstructive sleep apnea", "Obstructive sleep apnoea", "Sleep apnea syndrome", "Sleep apnoea syndrome", "Sleep apnea", "Sleep apnoea", "hypoapnea", "OSA", "Treatment", "Therapy", "Children", "Pediatric", "Craniofacial abnormalities", "Craniofacial anomalies", "Craniofacial abnormality", "Orthodontic" y una búsqueda retrógrada en los textos seleccionados. Resultados: Se incluyeron 23 artículos; 12 ensayos clínicos, 6 revisiones sistemáticas, 1 estudio observacional y 4 revisiones narrativas. Conclusión: Los tratamientos ortopédicos para el síndrome de apnea e hipoapnea son la expansión rápida maxilar y dispositivos de avance mandibular. No se encontró suficiente evidencia para determinar que estos dispositivos resuelvan completamente el síndrome, pero disminuyen el índice de apnea e hipoapnea y sus signos y síntomas.

ABSTRACT: Introduction: Obstructive sleep apnea and hypoapnea syndrome refers to a respiratory sleep disorder with an increased prevalence among children. There are many therapeutic alternatives, focused on controlling trigger factors and the signs and symptoms progression. The objective of this review is to describe the effects of the available treatments for sleep apnea and hypoapnea syndrome in children with sagittal and transverse intermaxillary anomalies. Materials and Method: An electronic search was performed in PubMed database, Epistemonikos, EBSCO, Tripdatabase, and The Cochrane Library, using the keywords "Obstructive sleep apnea", "Obstructive sleep apnoea", "Sleep apnea syndrome", "Sleep apnoea syndrome", "Sleep apnea", "Sleep apnoea", "hypoapnea", "OSA", "Treatment", "Therapy", "Children", "Pediatric", "Craniofacial abnormalities", "Craniofacial anomalies", "Craniofacial abnormality" and "Orthodontic". Also, a retrieval search in the selected articles references was performed. Results: 23 articles were included; 12 clinical trials, 6 systematic reviews, 1 observational study and 4 narrative reviews. Conclusion: There are two types of orthopedic treatment for sleep apnea and hypoapnea syndrome in children with sagittal and transverse intermaxillary anomalies: rapid maxillary expansion and mandibular advancement devices. There was not enough evidence to determine that these devices achieve the syndrome's complete resolution. An important decrease in the apnea and hypoapnea index and signs and symptoms were observed.

Posteromedial Hypothalamic Deep Brain Stimulation for Refractory Aggressiveness in a Patient With Weaver Syndrome: Clinical, Technical Report and Operative Video.

BACKGROUND AND IMPORTANCE: Deep brain stimulation of the posteromedial hypothalamus (PMH DBS) appears to be an effective treatment for drug-resistant aggressiveness. Weaver syndrome (WS) is a rare genetic disorder in which patients develop some degree of intellectual disability and rarely severe behavioral alterations that may benefit from this procedure. CLINICAL PRESENTATION: We present the case of a 26-yr-old man diagnosed with WS presenting with uncontrollable self and heteroaggressiveness and disruptive behavior refractory to pharmacological treatment and under severe physical and mechanical restraining measures. The patient was successfully treated with bilateral PMH DBS resulting in affective improvement, greater tolerance for signs of affection, regularization in his sleep pattern and appetite disturbances at 12-mo follow-up. A detailed description and video of the procedure are presented, and a review of the clinical characteristics of WS and the utility and benefits of PMH DBS for refractory aggressiveness are reviewed. CONCLUSION: To our knowledge, this is the first case of refractory aggressiveness described in WS as well as the first patient with WS successfully treated with PMH DBS.

A 9-month-old Chinese patient with Gabriele-de Vries syndrome due to novel germline mutation in the YY1 gene.

BACKGROUND: Gabriele-de Vries syndrome (GADEVS), also known as YY1 haploinsufficiency syndrome, is a very rare autosomal dominant neurodevelopmental disorder (NDD) due to YY1 mutation characterized by mild-to-profound developmental delay (DD)/intellectual disability (ID), a wide spectrum of functional and morphologic abnormalities, and intrauterine growth restriction or low birth weight and feeding difficulties are common in the patients. However, NDDs, such as language development disorder and ID, could hardly be assessed in patients younger than 2 years old. METHODS: We describe a 9-month-old female with DD, failure to thrive, and facial dysmorphism. Genetic analysis was conducted by whole exome sequencing (WES) and confirmed by Sanger sequencing. RESULTS: In addition to DD and dysmorphic facial features, this patient had urinary tract infection, acute pyelonephritis, bilateral vesicoureteral reflux (grade III), gastroesophageal reflux, and malnutrition. She was found to have foramen ovale or atrial septal defect, and enlarged left lateral ventricle in the brain. After performing WES, a novel heterozygous mutation NM_003403.5:c.1124G>A, p.Arg375Gln in the YY1 gene was identified. CONCLUSION: Our findings suggest that genetic tests are critical technique for diagnosis of GADEVS, especially in patients with early-childhood, unexplained developmental or growth disorders, thus, the prevalence of GADEVS may be underestimated. The clinical features and identified YY1 mutation in our patient expand the spectra of phenotypes and genotypes of GADEVS, respectively.

3D CT Soft Tissue Craniofacial Analysis and Lip Morphology

ABSTRACT Objctive: To assess the soft tissue characteristics of Bangladeshi adults to formulate soft tissue 3D CT standards using Holdaway's (HA) and lip morphology (LM) analyses. Another aim of this study was to assess the gender dimorphism of Bangladeshi population. Material and Methods: One hundred and seventeen (Eighty-five men and Thirty-two women) Bangladeshi adults have obtained their computed tomography (CT) scan at the Radiology Department for normal diagnosis. Craniofacial deformities were undetected in all cases. The CT images were prepared by a 3D imaging programming software (Mimics 11.02 Materialise). Parameters from the identified landmark points were measured in 3D through this software. Results: Upper lip thickness (ULT) (vermillion UL-A point) measurement was significant in HA and in LM analyses, upper lip protrusion (ULP) (Ls to Sn-SPog) measurement has demonstrated significant difference among both genders, where p-value was less than 0.05. Mean measurements of Bangladeshi adults were relatively comparable except the face convexity (FC) when compared with the HA cephalometric soft tissue values. Conclusion: By using HA and LM analyses, 3D CT soft tissue standards were established for Bangladeshi adults. Measurements for all parameters have remained equivalent with the HA standard data apart from the FC measurement. This consequently may demonstrate that the Bangladeshi population retains a convex shape with a slight protrusive lip or retruded chin.

Efficacy of orthodontic and orthognathic treatment for oral and maxillofacial deformities.

BACKGROUND: This study aims to assess the efficacy and safety of orthodontic and orthognathic treatment (OOT) for patients with oral and maxillofacial deformities (OMDF) systematically. METHODS: This study will comprehensively search Cochrane Library, PubMed, EMBASE, Scopus, Web of Science, PsycINFO, Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from their inceptions to the July 1, 2019. Grey literature will be explored via searching dissertations, Google scholar and conference abstracts. Two team members will independently perform all citations, data extraction, and methodological quality. We will also utilize RevMan 5.3 Software for statistical analysis. RESULTS: This study will provide high quality evidence of OOT for OMDF. The primary outcomes consist of number of patients cured; proportion of patients healed; and time to complete healing within trial period. Secondary outcomes include quality of life (often assessed as any relevant scales, such as 36-Item Short Form Survey), costs, and complications. CONCLUSION: This study will provide evidence for judging whether OOT is effective treatment for OMDF. SYSTEMATIC REVIEW REGISTRATION: CRD42019144610.

Maternal choline supplementation mitigates alcohol-induced fetal cranio-facial abnormalities detected using an ultrasonographic examination in a sheep model.

Early detection of prenatal alcohol exposure is critical for designing and testing effectiveness of interventional therapeutics. Choline supplementation during and after prenatal alcohol exposure has shown promising benefits in improving outcomes in rodent models and clinical studies. A sheep model of first trimester-equivalent binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Pregnant sheep were randomly assigned to six groups: Saline + Placebo control, Saline + Choline, binge Alcohol + Placebo (light binging), binge Alcohol + Choline, Heavy binge Alcohol + Placebo (heavy binging), and Heavy binge Alcohol + Choline. Ewes received intravenous alcohol or saline on three consecutive days per week from gestation day (GD) 4-41 to mimic a first trimester-equivalent weekend binge-drinking paradigm. Choline (10 mg/kg in the daily food ration) was administered from GD 4 until term. On GD 76, 11 fetal ultrasonographic measurements were collected transabdominally. Heavy binge alcohol exposure reduced fetal Frontothalamic Distance (FTD), Mean Orbital Diameter (MOD), and Mean Lens Diameter (MLD), and increased Interorbital Distance (IOD) and Thalamic Width (TW). Maternal choline supplementation mitigated most of these alcohol-induced effects. Maternal choline supplementation also improved overall fetal femur and humerus bone lengths, compared to their respective placebo groups. Taken together, these results indicate a potential dose-dependent effect that could impact the sensitivity of these ultrasonographic measures in predicting prenatal alcohol exposure. This is the first study in the sheep model to identify biomarkers of prenatal alcohol exposure in utero with ultrasound and co-administration of maternal choline supplementation.

Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds.

The EU-EuroMix project adopted the strategy of the European Food Safety Authority (EFSA) for cumulative risk assessment, which limits the number of chemicals to consider in a mixture to those that induce a specific toxicological phenotype. These so-called cumulative assessment groups (CAGs) are refined at several levels, including the target organ and specific phenotype. Here, we explore the zebrafish embryo as a test model for quantitative evaluation in one such CAG, skeletal malformations, through exposure to test compounds 0-120 hpf and alcian blue cartilage staining at 120 hpf, focusing on the head skeleton. Reference compounds cyproconazole, flusilazole, metam, and thiram induced distinctive phenotypes in the head skeleton between the triazoles and dithiocarbamates. Of many evaluated parameters, the Meckel's-palatoquadrate (M-PQ) angle was selected for further assessment, based on the best combination of a small confidence interval, an intermediate maximal effect size and a gentle slope of the dose-response curve with cyproconazole and metam. Additional test compounds included in the CAG skeletal malformations database were tested for M-PQ effects, and this set was supplemented with compounds associated with craniofacial malformations or cleft palate to accommodate otherwise organized databases. This additional set included hexaconazole, all-trans-retinoic acid, AM580, CD3254, maneb, pyrimethanil, imidacloprid, pirimiphos-methyl, 2,4-dinitrophenol, 5-fluorouracil, 17alpha-ethynylestradiol (EE2), ethanol, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), PCB 126, methylmercury, boric acid, and MEHP. Most of these compounds produced a dose-response for M-PQ effects. Application of the assay in mixture testing was provided by combined exposure to cyproconazole and TCDD through the isobole method, supporting that in this case the combined effect can be modeled through concentration addition.

Association Between Prenatal Alcohol Exposure and Craniofacial Shape of Children at 12 Months of Age.

Importance: Children who receive a diagnosis of fetal alcohol spectrum disorder may have a characteristic facial appearance in addition to neurodevelopmental impairment. It is not well understood whether there is a gradient of facial characteristics of children who did not receive a diagnosis of fetal alcohol spectrum disorder but who were exposed to a range of common drinking patterns during pregnancy. Objective: To examine the association between dose, frequency, and timing of prenatal alcohol exposure and craniofacial phenotype in 12-month-old children. Design, Setting, and Participants: A prospective cohort study was performed from January 1, 2011, to December 30, 2014, among mothers recruited in the first trimester of pregnancy from low-risk, public maternity clinics in metropolitan Melbourne, Australia. A total of 415 white children were included in this analysis of 3-dimensional craniofacial images taken at 12 months of age. Analysis was performed with objective, holistic craniofacial phenotyping using dense surface models of the face and head. Partial least square regression models included covariates known to affect craniofacial shape. Exposures: Low, moderate to high, or binge-level alcohol exposure in the first trimester or throughout pregnancy. Main Outcomes and Measures: Anatomical differences in global and regional craniofacial shape between children of women who abstained from alcohol during pregnancy and children with varying levels of prenatal alcohol exposure. Results: Of the 415 children in the study (195 girls and 220 boys; mean [SD] age, 363.0 [8.3] days), a consistent association between craniofacial shape and prenatal alcohol exposure was observed at almost any level regardless of whether exposure occurred only in the first trimester or throughout pregnancy. Regions of difference were concentrated around the midface, nose, lips, and eyes. Directional visualization showed that these differences corresponded to general recession of the midface and superior displacement of the nose, especially the tip of the nose, indicating shortening of the nose and upturning of the nose tip. Differences were most pronounced between groups with no exposure and groups with low exposure in the first trimester (forehead), moderate to high exposure in the first trimester (eyes, midface, chin, and parietal region), and binge-level exposure in the first trimester (chin). Conclusions and Relevance: Prenatal alcohol exposure, even at low levels, can influence craniofacial development. Although the clinical significance of these findings is yet to be determined, they support the conclusion that for women who are or may become pregnant, avoiding alcohol is the safest option.

Fetal Valproate Syndrome.

BACKGROUND: There have been several reports of congenital malformations in the offspring of mothers who took valproic acid (VPA) during pregnancy as a treatment for epilepsy. METHODS: Herein, we describe four cases with typically similar facial features of fetal valproate syndrome accompanied to minor skeletal abnormalities. RESULTS: The first case was a 16-month-old girl, presenting with facial dysmorphism, and finger abnormalities. Her mother took VPA (1500 mg/d) up to the 10th gestational week and at a dosage of 1000 mg/d through the pregnancy. The second patient was 5-year-old boy with speech disability, bilateral cryptorchidism, facial dysmorphism, and finger abnormalities whose mother took VPA (1000 mg/d) through pregnancy. The third 19-month-old patient was the brother of the second patient who had facial dysmorphism, bilateral cryptorchidism, and finger abnormalities. His mother also took VPA (1000 mg/d) through pregnancy. The fourth 3-year and 6 month-old boy with minor facial dysmorphism and sternum deformity was exposed to VPA (500 mg/d) in utero. CONCLUSION: In conclusion, there is a recognizable spectrum of abnormalities in some infants exposed to VPA without dose-depence and the common facial dysmorphic features and minor skeletal abnormalities that may occur within the both low and high dose VPA use.

Diagnosis of infant synostotic and nonsynostotic cranial deformities: a review for pediatricians / Diagnóstico das deformidades cranianas sinostóticas e não sinostóticas em bebês: uma revisão para pediatras

Abstract Objective: To review the current comprehensive care for nonsyndromic craniosynostosis and nonsynostotic cranial deformity and to offer an overall view of these craniofacial conditions. Data source: The review was conducted in the PubMed, SciELO, and LILACS databases without time or language restrictions. Relevant articles were selected for the review. Data synthesis: We included the anatomy and physiology of normal skull development of children, discussing nuances related to nomenclature, epidemiology, etiology, and treatment of the most common forms of nonsyndromic craniosynostosis. The clinical criteria for the differential diagnosis between positional deformities and nonsyndromic craniosynostosis were also discussed, giving to the pediatrician subsidies for a quick and safe clinical diagnosis. If positional deformity is accurately diagnosed, it can be treated successfully with behavior modification. Diagnostic doubts and craniosynostosis patients should be referred straightaway to a multidisciplinary craniofacial center. Conclusions: Pediatricians are in the forefront of the diagnosis of patients with cranial deformities. Thus, it is of paramount importance that they recognize subtle cranial deformities as it may be related to premature fusion of cranial sutures.

Resumo Objetivo: Revisar o atendimento integral atual de craniossinostose não sindrômica e deformidade craniana não sinostótica e oferecer uma visão global dessas condições craniofaciais. Fontes de dados: A revisão foi feita nas bases de dados PubMed, SciELO e Lilacs e sem restrições de tempo ou idioma. Artigos relevantes foram selecionados para a revisão. Síntese dos dados: Foram incluídas a anatomia e a fisiologia do desenvolvimento normal do crânio em crianças, discutidas nuances relacionadas à nomenclatura, epidemiologia, etiologia e ao tratamento das formas mais comuns de craniossinostose não sindrômica. Também foram discutidos os critérios clínicos para o diagnóstico diferencial entre deformidades posicionais e craniossinostose não sindrômica. Deram-se aos pediatras subsídios para um diagnóstico clínico rápido e seguro. Se deformidades posicionais forem diagnosticadas com precisão, elas podem ser tratadas com sucesso por meio da modificação do comportamento. Dúvidas de diagnóstico e pacientes portadores de craniossinostose devem ser encaminhados imediatamente a um centro multidisciplinar craniofacial. Conclusões: Os pediatras estão na vanguarda do diagnóstico de pacientes com deformidades cranianas. Assim, é de suma importância que reconheçam deformidades cranianas sutis, pois elas podem estar relacionadas à fusão prematura das suturas cranianas.

Dietary phosphate supplement does not rescue skeletal phenotype in a mouse model for craniometaphyseal dysplasia.

BACKGROUND: Mutations in the human progressive ankylosis gene (ANKH; Mus musculus ortholog Ank) have been identified as cause for craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. We previously reported a knock-in (KI) mouse model (Ank KI/KI) for CMD and showed transiently lower serum phosphate (Pi) as well as significantly higher mRNA levels of fibroblast growth factor 23 (Fgf23) in Ank KI/KI mice. FGF23 is secreted by bone and acts in kidney to promote Pi wasting which leads to lower serum Pi levels. Here, we examined whether increasing the Pi level can partially rescue the CMD-like skeletal phenotype by feeding Ank +/+ and Ank KI/KI mice with high Pi (1.7 %) diet from birth for 6 weeks. We studied the Pi metabolism in Ank KI/KI mice and CMD patients by examining the Pi regulators FGF23 and parathyroid hormone (PTH). RESULTS: High Pi diet did not correct CMD-like features, including massive jawbone, increased endosteal and periosteal perimeters and extensive trabeculation of femurs in Ank KI/KI mice shown by computed microtomography (µCT). This unexpected negative result is, however, consistent with normal serum/plasma levels of the intact/active form of FGF23 and PTH in Ank KI/KI mice and in CMD patients. In addition, FGF23 protein expression was unexpectedly normal in Ank KI/KI femoral cortical bone as shown by immunohistochemistry despite increased mRNA levels for Fgf23. Renal expression of genes involved in the FGF23 bone-kidney axis, including mFgfr1, mKlotho, mNpt2a, mCyp24a1 and m1αOHase, were comparable between Ank +/+ and Ank KI/KI mice as shown by quantitative real-time PCR. Different from normal FGF23 and PTH, serum 25-hydroxyvitamin D was significantly lower in Ank KI/KI mice and vitamin D insufficiency was found in four out of seven CMD patients. CONCLUSIONS: Our data suggests that FGF23 signaling and Pi metabolism are not significantly affected in CMD and transiently low Pi level is not a major contributor to CMD.

Relationship between the cranial base and the mandible in artificially deformed skulls.

OBJECTIVES: There is controversy regarding the relationship between mandibular position and alterations of the cranial base that provoke a more anterior location of the glenoid fossa. Artificially deformed skulls display marked alterations of the cranial base. This study evaluates mandibular changes as function of the morphology of the cranial base in these skulls. MATERIAL AND METHODS: A geometric morphometric study was performed on lateral cephalometric X-rays of three groups of skulls: 32 with anteroposterior deformity, 17 with circumferential deformity and 39 with no apparent deformity. RESULTS: In artificially deformed skulls, the cranial base was deformed causing the mandibular condyle to be in a more anterior position. There was a complete remodelling of the mandible involving narrowing and elongation of the mandibular ramus, rotation of the corpus of the mandible and increased vertical height of the symphysis. Forward displacement did not occur. Integration between mandible and cranial base is not altered by deformation of the skull. CONCLUSIONS: Deformity of the cranial vault exerts an influence on the mandible, supporting the theory of modular units in complete integration. This also supports the theory that mandibular prognathism is a multifactorial result and not a direct effect of displacement of the cranial base.

Diagnosis of infant synostotic and nonsynostotic cranial deformities: a review for pediatricians. / Diagnóstico das deformidades cranianas sinostóticas e não sinostóticas em bebês: uma revisão para pediatras.

OBJECTIVE: To review the current comprehensive care for nonsyndromic craniosynostosis and nonsynostotic cranial deformity and to offer an overall view of these craniofacial conditions. DATA SOURCE: The review was conducted in the PubMed, SciELO, and LILACS databases without time or language restrictions. Relevant articles were selected for the review. DATA SYNTHESIS: We included the anatomy and physiology of normal skull development of children, discussing nuances related to nomenclature, epidemiology, etiology, and treatment of the most common forms of nonsyndromic craniosynostosis. The clinical criteria for the differential diagnosis between positional deformities and nonsyndromic craniosynostosis were also discussed, giving to the pediatrician subsidies for a quick and safe clinical diagnosis. If positional deformity is accurately diagnosed, it can be treated successfully with behavior modification. Diagnostic doubts and craniosynostosis patients should be referred straightaway to a multidisciplinary craniofacial center. CONCLUSIONS: Pediatricians are in the forefront of the diagnosis of patients with cranial deformities. Thus, it is of paramount importance that they recognize subtle cranial deformities as it may be related to premature fusion of cranial sutures.